PROJECT SUMMARY (JEONG, JI) Integration of the implanted biomaterials with the recipient tissue with minimal foreign body reaction is of paramount importance for both medical implants (to permanently replace damaged tissues) and tissue engineering scaffolds (to regenerate damaged tissues). It is desired that the implanted material is not only biocompatible but also establish stable mechanical connection with the surrounding tissue. Monocyte-derived macrophages of the innate immune system are known to be one of the main players in orchestrating inflammatory response and the ensuing wound healing process around the material. Recent studies have confirmed various material parameters, such as surface chemistry, pore size and mechanical stiffness, as factors modulating the phenotypes of macrophages on the materials both in vitro and in vivo. However, systematic in vitro studies are lacking in literature on how the phenotypic response of macrophages and their cytokine release as a function of various material parameters affect other types of cells participating in the material integration. Most in vitro studies to date have focused on the polarization of macrophages on different materials, but did not address how such polarization affects the functions of other cell types. The overall objective of the current proposal is to provide fundamental understanding of the interplay between macrophages and other functional cells on microporous polymeric materials and to provide design principles for better integration of implanted biomaterials. For this, human dermal fibroblasts (DFs) and human mesenchymal stem cells (MSCs) will be cultured on polymeric microporous scaffolds with varying surface chemistries in the absence and presence of macrophages. The specific aims of this project are (1) assessing proliferation, differentiation and ECM secretion by DFs and MSCs on microporous scaffolds of well-defined pore sizes and surface chemistries (2) assessing proliferation, differentiation and ECM secretion by DFs and MSCs in the presence of macrophages (3) in vivo assay of tissue integration of microporous scaffolds. Completion of these specific aims will provide clear mechanistic understanding of the macrophage polarization as a function of material design parameters and how that affects various cellular functions of other cell types that are relevant to material-tissue integration. We will gain improved design principles for developing medical implants and tissue engineering scaffolds that highly integrate with tissues.